Method for producing enantiomeric form of 2,3-diaminopropionic acid derivatives

ABSTRACT

The invention relates to a method for producing enantiomeris form of 2, 3-diaminopropionic acid derivatives of formula (I) by asymetric hydrogenation from compounds of formula (II).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority from InternationalApplication No. PCT/EP2005/006920 filed on Jun. 28, 2005, from which thepresent application is a continuation, which claims the benefit ofpriority from German Application No. 10 2004 033 406.4, filed on Jul.10, 2004.

FIELD OF INVENTION

The invention relates to a process for preparing the enantiomeric formsof 2,3-diaminopropionic acid derivatives of the formula I by asymmetrichydrogenation. The compounds of the formula I are suitable intermediatesfor preparing IkB kinase inhibitors (WO 01/30774 A1; WO 2004/022553).

BACKGROUND OF THE INVENTION

It is known that α,β-diaminopropionic acid derivatives can be preparedby Rh-catalyzed asymmetric hydrogenation according to Scheme 1 (J OrgChem, Vol. 66, 11, 2001, pages 4141-4147). However, the asymmetrichydrogenation succeeds only when both nitrogen atoms have been acylated.

The attempt to hydrogenate N,N-dimethyleneamines orN,N-dimethylene-enamines was without success.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that the asymmetric synthesis succeeds even forcompounds of the formula II. The synthesis of the compound of theformula I succeeds with high yields and high enantioselectivity.

The invention therefore relates to a process for obtaining the compoundof the formula I

where R1 and R2 are the same or different and are each independently

1) a hydrogen atom,

2) —(C₁-C₄)-alkyl,

3) —(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-, di- ortrisubstituted independently by R11, where R11 is

-   -   a) F, Cl, I or Br,    -   b) —(C₁-C₄)-alkyl,    -   c) —CN,    -   d) —CF₃,    -   e) —OR⁵ in which R⁵ is a hydrogen atom or —(C₁-C₄)-alkyl,    -   f) —N(R⁵)—R⁶ in which R⁵ and R⁶ are each independently a        hydrogen atom or —(C₁-C₄)-alkyl,    -   g) —C(O)—R⁵ in which R⁵ is a hydrogen atom or —(C₁-C₄)-alkyl, or    -   h) —S(O)_(x)—R⁵ in which x is the integer zero, 1 or 2, and R⁵        is a hydrogen atom or —(C₁-C₄)-alkyl,

4) —CH(R7)-aryl in which aryl is unsubstituted or mono-, di- ortrisubstituted independently by —NO₂, —O—CH₃, F, Cl or bromine, where R7is a hydrogen atom or —(C₁-C₄)-alkyl, or

5) a 4- to 15-membered Het ring where the Het ring is unsubstituted ormono-, di- or trisubstituted independently by —(C₁-C₅)-alkyl,—(C₁-C₅)-alkoxy, halogen, nitro, amino, trifluoro-methyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl,cyano, hydroxycarbonyl, amino-carbonyl or —(C₁-C₄)-alkoxycarbonyl,

R3 is

-   -   1 ) a hydrogen atom,    -   2) —(C₁-C₄)-alkyl,    -   3) —(C₆-C₁₄)-aryl in which aryl is unsubstituted or mono-, di-        or trisubstituted independently by —NO₂, —O—(C₁-C₄)-alkyl, F, Cl        or bromine,    -   4) —O—C(CH₃)₃, or    -   5) —O—CH(R7)-aryl in which aryl is unsubstituted or mono-, di-        or trisubstituted independently by —NO₂, —O—CH₃, F, Cl or        bromine, where R7 is a hydrogen atom or —(C₁-C₄)-alkyl,        R4 is    -   1) a hydrogen atom,    -   2) —(C₁-C₄)-alkyl or    -   3) —CH(R8)-aryl in which R8 is a hydrogen atom or        —(C₁-C₄)-alkyl,        which comprises hydrogenating a compound of the formula II

in which R1, R2, R3 and R4 are each as defined in the formula I and thecompound may be present in the E or in the Z configuration on the doublebond,in the presence of hydrogen and a catalyst.

The invention further relates to a process for obtaining the compound ofthe formula I

where R1 is phenyl or a hydrogen atom,

R2 is phenyl, pyridyl or thiazolyl, in which phenyl, pyridyl orthiazolyl is unsubstituted or substituted by fluorine or chlorine, and

R3 is phenyl or —O—CH₂-phenyl and

R4 is methyl or ethyl.

The invention further relates to a process for obtaining the compound ofthe formula

or salts thereof in which R1, R2 and R4 are each as defined in theformula I,which comprises

a) hydrogenating the compound of the formula II

-   -   in which R1, R2, R3 and R4 are each as defined in the formula I,    -   in the presence of hydrogen and a catalyst, and converting it to        a compound of the formula I

-   -   and

b) converting the resulting compound of the formula I to a compound ofthe formula III.

Process step b) is performed, for example, according to the reactionconditions as described by T. Greene, P. Wuts in Protective Groups inOrganic Synthesis, Wiley-Interscience, for the cleavage of amides orcarbamates. Depending on the reaction conditions selected, here stronglybasic reaction conditions in particular, the direct conversion ofcompounds of the formula I to compounds of the formula III leads toracemization of the chiral center formed by the asymmetric hydrogenationor to other undesired side reactions. This can be prevented when thecompound of the formula I is converted to the compound IV with, forexample, tert-butyl dicarbonate or another reagent for the introductionof tert-butoxycarbonyl protecting groups. The tert-butoxycarbonylprotecting group is introduced in a suitable solvent such asacetonitrile, tetrahydrofuran or toluene, preferably with the aid of anacylation catalyst such as N,N-dimethylaminopyridine (DMAP). Thereaction temperature is from 0° C. to 120° C., preferably from 20° C. to40° C.

The reaction time is generally from 0.5 to 24 hours, depending on thecomposition of the mixture and the temperature range selected. Theresulting compound of the formula IV is then converted to a compound ofthe formula la under mild conditions, such as magnesium methoxide. Theconversion to the compounds of the formula III is typically done underreaction conditions known from the literature, as described by T.Greene, P. Wuts in Protective Groups in Organic Synthesis,Wiley-Interscience, for the cleavage of tert-butyloxycarbonyl (BOC)protecting groups.

The invention therefore further relates to a process for obtaining thecompound of the formula III,

which comprises

a) hydrogenating the compound of the formula II in which R1, R2, R3 andR4 are each as defined in the formula I in the presence of hydrogen anda catalyst and converting it to a compound of the formula I,

b) reacting the resulting compound of the formula I with a tert-butyldicarbonate and an acylation catalyst such as dimethylaminopyridine(DMAP) to give a compound of the formula IV

-   -   in which R1, R2, R3 and R4 are each as defined in formula I,

c) then converting the resulting compound of the formula IV to thecompound of the formula Ia

-   -   in which R1, R2, R3 and R4 are each as defined in formula I, and

d) converting the resulting compound of the formula Ia to the compoundof the formula III or salts thereof, in which R1, R2 and R4 are each asdefined in formula I.

The conversion of the compounds of the formula IV to the compound of theformula la is achieved, for example, by treatment with bases, such aslithium hydroxide, hydrazine or magnesium methoxide (literature: J. Org.Chem. 1997, 62, 7054-7057). The tert-butyloxycarbonyl group is detachedto give compounds of the formula III under standard conditions, such astreatment with trifluoroacetic acid (TFA), hydrochloric acid orp-toluenesulfonic acid in suitable solvents.

The undesired enantiomer is depleted by crystallization of the compoundsof the formula I or III from suitable solvents such as methanol,ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol and estersthereof. In the case of compounds of the formula III, thecrystallization is preferably performed in the form of their (acidic)salts such as hydrochloride, methanesulfonate or p-toluenesulfonate.Under these conditions, optical purities of >99% are achieved.Appropriately, the entire reaction sequence can be performed in aone-pot process without isolation of the compounds IV and Ia. The yieldsand optical purities achieved here correspond to the values mentionedabove.

The term “catalyst” refers to compounds as described, for example, by E.N. Jacobson, A. Pfaltz, H. Yamamoto in Comprehensive AsymmetricCatalysis, Springer-Verlag, 1999 or X. Zhang, Chemical Reviews, 2003,103, 3029-3069 and the literature cited there, for example opticallyactive rhodium, ruthenium or iridium complexes or mixtures thereof. Thecatalytically active complex is formed by reaction of a metal complexwith an optically active phosphine. In the case of the above-describedacylated 2,3-diaminopropionic acid derivatives, the Me-Duphos orEt-Duphos-rhodium complexes exhibited very good enantioselectivities andconversions. It is also known that chiral β-amino acids can be preparedby using rhodium complexes of the BICP, t-Bu-BisP, BDPMI, Et-FerroTANE,MaIPHOS and MonoPHOS type as catalysts.

The terms “—(C₁-C₄)-alkyl” or “—(C₁-C₅)-alkyl” are understood to meanhydrocarbon radicals whose carbon chain is straight-chain or branchedand contains from 1 to 4 or from 1 to 5 carbon atoms, for examplemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl.

The terms “—CH(R7)—” or “—CH(R8)—” are understood to mean straight-chainor branched hydrocarbon radicals such as methylene, ethylene,isopropylene, isobutylene or pentylene. For example, in the case that R7is a hydrogen atom and aryl is phenyl, the “—CH(R7)-aryl” radical is thebenzyl radical.

The terms “—(C₆-C₁₄)-aryl” or “aryl” are understood to mean aromaticcarbon radicals having from 6 to 14 carbon atoms in the ring.—(C₆-C₁₄)-Aryl radicals are, for example, phenyl, naphthyl, for example1-naphthyl, 2-naphthyl, anthryl or fluorenyl. Naphthyl radicals and inparticular phenyl radicals are preferred aryl radicals.

The term “4- to 15-membered Het ring” is understood to mean ring systemshaving from 4 to 15 carbon atoms, which are present in one, two or threering systems bonded to one another and which contain one, two, three orfour identical or different heteroatoms from the group of oxygen,nitrogen or sulfur. Examples of these ring systems are the acridinyl,azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl,benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl,dibenzothiophenyl, dihydrofuran[2,3-b]tetrahydrofuranyl, dihydrofuranyl,dioxolyl, dioxanyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl),isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl,isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl radicals.

The asterisk on a carbon atom in the compound of the formula I or IImeans that the particular carbon atom is chiral and that the compound ispresent either as the R- or S-enantiomer.

The asymmetric hydrogenation of the compounds of the formula II isadvantageously performed at a temperature of from 10° C. to 200° C. anda hydrogen pressure of from 1 bar to 200 bar. The molarcatalyst-reactant ratio is advantageously from 1:100 to 1:10 000.Suitable solvents for the asymmetric hydrogenation are, for example,water, lower alcohols such as methanol, ethanol, propanol orisopropanol, aromatic hydrocarbons such as toluene, ketones such asacetone, halogenated hydrocarbons such as dichloromethane, carboxylicesters such as ethyl acetate, and ethers such as tetrahydrofuran.

The optically active 2,3-diaminopropionic acid derivatives of theformula I, III and IV as such, including in the form of their enantiomermixtures and their salts, likewise form part of the subject matter ofthe present invention. Enantiomer mixtures should be understood here tomean in particular those in which one enantiomer is enriched compared tothe other.

The compounds of the formula II are either known or can be prepared, forexample, by reacting compounds of the formula IV in which R3 and R4 areeach as defined above with an amine of the formula V in which R1 and R2are each as defined above.

The reaction temperature is from 0° C. to 120° C., preferably from 20°C. to 60° C.

The reaction time is generally from 0.5 to 8 hours, depending on thecomposition of the mixture and the selected temperature range. Theresulting compound of the formula II is then removed from the reactionmixture by aqueous workup and extraction with a suitable solvent, forexample ethyl acetate or dichloromethane, or by crystallization.

A further aspect of the invention relates to novel compounds of theformula II where R1 and R2 are the same or different and are eachindependently

1) —(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-, di- ortrisubstituted independently by R11, where R11 is

-   -   a) F, Cl, I or Br,    -   b) —(C₁-C₄)-alkyl,    -   c) —CN,    -   d) —CF₃,    -   e) —OR⁵ in which R⁵ is a hydrogen atom or —(C₁-C₄)-alkyl,    -   f) —N(R⁵)—R⁶ in which R⁵ and R⁶ are each independently a        hydrogen atom or —(C₁-C₄)-alkyl,    -   g) —C(O)—R⁵ in which R⁵ is a hydrogen atom or —(C₁-C₄)— alkyl,        or    -   h) —S(O)_(x)—R5 in which x is the integer zero, 1 or 2, and R⁵        is a hydrogen atom or —(C₁-C₄)-alkyl, or

2) a 4- to 15-membered Het ring where the Het ring is unsubstituted ormono-, di- or trisubstituted independently by —(C₁-C₅)-alkyl,—(C₁-C₅)-alkoxy, halogen, nitro, amino, trifluoro-methyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl,cyano, hydroxycarbonyl, amino-carbonyl or —(C₁-C₄)-alkoxycarbonyl,

R3 is

-   -   1) —(C₆-C₁₄)-aryl in which aryl is unsubstituted or mono-, di-        or trisubstituted independently by —NO₂, —O—(C₁-C₄)-alkyl, F, Cl        or bromine,    -   2) —O—C(CH₃)₃, or 3) —O—CH(R7)-aryl in which aryl is        unsubstituted or mono-, di- or trisubstituted independently by        —NO₂, —O—CH₃, F, Cl or bromine, in which R7 is a hydrogen atom        or —(C₁-C₄)-alkyl,        R4 is    -   1) a hydrogen atom,    -   2) —(C₁-C₄)-alkyl or    -   3) —CH(R8)-aryl in which R8 is a hydrogen atom or        —(C₁-C₄)-alkyl.

A further aspect of the invention relates to novel compounds of theformula IV

where R1 and R2 are the same or different and are each independently

1) —(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-, di- ortrisubstituted independently by R11,

-   -   where R11 is    -   a) F, Cl, I or Br,    -   b) —(C₁-C₄)-alkyl,    -   c) —CN,    -   d) —CF₃,    -   e) —OR⁵ in which R⁵ is a hydrogen atom or —(C₁-C₄)-alkyl,    -   f) —N(R⁵)-R⁶ in which R⁵ and R⁶ are each independently a        hydrogen atom or —(C₁-C₄)-alkyl,    -   g) —C(O)—R⁵ in which R⁵ is a hydrogen atom or —(C₁-C₄)-alkyl, or    -   h) —S(O)_(x)—R⁵ in which x is the integer zero, 1 or 2, and R⁵        is a hydrogen atom or —(C₁-C₄)-alkyl, or

2) a 4- to 15-membered Het ring where the Het ring is unsubstituted ormono-, di- or trisubstituted independently by —(C₁-C₅)-alkyl,—(C₁-C₅)-alkoxy, halogen, nitro, amino, trifluoro-methyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl,cyano, hydroxycarbonyl, amino-carbonyl or —(C₁-C₄)-alkoxycarbonyl,

R3 is

-   -   1) —(C₆-C₁₄)-aryl in which aryl is unsubstituted or mono-, di-        or trisubstituted independently by —NO₂, —O—(C₁-C₄)-alkyl, F, Cl        or bromine,    -   2) —O—C(CH₃)₃, or    -   3) —O—CH(R7)-aryl in which aryl is unsubstituted or mono-, di-        or trisubstituted independently by —NO₂, —O—CH₃, F, Cl or        bromine,        in which R7 is a hydrogen atom or —(C₁-C₄)-alkyl,        R4 is    -   1) a hydrogen atom,    -   2) —(C₁-C₄)-alkyl or    -   3) -CH(R8)-aryl        in which R8 is a hydrogen atom or —(C₁-C₄)-alkyl.

The invention therefore further relates to a process for obtaining thenovel compounds of the formula IV, which comprises

a) hydrogenating the compound of the formula II, in which R1, R2, R3 andR4 are each as defined in the novel compound of the formula II, in thepresence of hydrogen and a catalyst and converting it to a compound ofthe formula I, and

b) reacting the resulting compound of the formula I with a tert-butyldicarbonate and an acylation catalyst such as dimethylaminopyridine(DMAP) to give a compound of the formula IV

-   -   in which R1, R2, R3 and R4 are each as defined in the novel        compound of the formula II.

The compounds of the formulae I, II, III and IV are suitable asintermediates for the preparation of IkB kinase inhibitors (WO 01/30774A1).

The invention is illustrated in detail hereinafter with reference toexamples. End products are generally determined by ¹H NMR (400 MHz, inDMSO-D6); in each case, the main peak or the two main peaks arereported. Temperatures are reported in degrees Celsius; RT means roomtemperature (22° C. to 26° C.). Abbreviations used are either explainedor correspond to the usual conventions.

EXAMPLES Example 1 Preparation of methyl2-benzoylamino-3-diphenylaminoacrylate

66 g (266 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 50g (295 mmol) of diphenylamine were dissolved at 40° C. in 1300 ml ofisopropanol. The solution was admixed with 60 ml (725 mmol) ofconcentrated hydrochloric acid within 5 minutes (min) and stirred for afurther 10 min. 550 ml of solvent were evaporated off under reducedpressure, the suspension was cooled to 10° C. and the crystallizedproduct was filtered off.Yield: 83.5 g (84% of theory)1H NMR: 3.62 (s, 3H), 6.95-7.10 (m, 6H), 7.20-7.30 (m, 8H), 7.32-7.40(m, 1H), 7.61 (s, 1H), 8.70 (s, 1H)

Example 2 Preparation of methyl2-benzyloxycarbonylamino-3-diphenylaminoacrylate

36 g (129 mmol) of methyl2-benzyloxycarbonylamino-3-dimethylaminoacrylate and 24.12 g (142 mmol)of diphenylamine were dissolved in 630 ml of isopropanol at 40° C.Subsequently, the solution was admixed with 17.4 ml of concentratedhydrochloric acid within 5 min and stirred at 40° C. for a further 30min. The reaction solution was concentrated to 300 ml and admixed slowlywith 300 ml of water. The crystallized product was filtered off withsuction and dried at 40° C. under reduced pressure.Yield: 30.5 g (59% of theory)1H NMR: 3.62 (s, 3H), 4.68 (s, 2H), 6.95-7.10 (m, 6H), 7.20-7.50 (m,9H), 7.61 (s,1 H)

Example 3 Preparation of racemic methyl2-benzoylamino-3-diphenylaminopropionate

With exclusion of oxygen, an autoclave was charged with 1 g (2.68 mmol)of methyl 2-benzoylamino-3-diphenylaminoacrylate and 40 mg (0.042 mmol)of tris(triphenylphosphine)rhodium(l) chloride. After purging withargon, 40 ml of oxygen-free methanol were added. The autoclave wassealed gas-tight and the solution was hydrogenated at RT for 20 hours(h). The autoclave was decompressed and purged with nitrogen. Thesolvent was evaporated off under reduced pressure and the residue waschromatographed through a column filled with silica gel 60 (eluent: 1:1ethyl acetate/heptane). After the solvents had been evaporated off underreduced pressure, a white solid remained, which was utilized for theformulation of a method and as a system test for the determination ofthe enantiomeric purity by HPLC on chiral phase.

HPLC column: Chiralpak OD 4 × 250 Eluent: 45:2:1  hexane/EtOH/MeOH +0.1% diethylamine Temperature: 30° C. Reactant retention time: 13.2minutes S-Isomer retention time: 11.8 minutes R-Isomer retention time:14.2 minutes Yield:  0.5 g (50% of theory) 1H NMR: 3.62 (s, 3H),4.15-4.35 (m, 2H), 4.75-4.90 (m, 1H), 6.90-7.05 (m, 6H), 7.20-7.30 (m,4H), 7.40-7.48 (m, 2H), 7.50-7.60 (m, 1H), 7.70-7.78 (d, 2H), 8.85 (d,1H)

Example 4 Preparation of methyl(S)-2-benzoylamino-3-diphenylaminopropionate

With exclusion exclusion of oxygen and moisture, an ampule was chargedwith 100 mg of methyl 2-benzoylamino-3-diphenylaminoacrylate (0.255mmol) and 1.9 mg (0.0026 mmol, 0.01 equivalent) of[(S,S)-Et-FerroTANE-Rh]BF₄. After purging with argon, 5 ml ofoxygen-free methanol were added. The ampule was sealed gas-tight andhydrogenated in an autoclave at 20 bar of hydrogen pressure for 24 h.The autoclave was decompressed and purged with nitrogen. The conversionof the hydrogenation was determined by HPLC. The enantioselectivity wasdetermined by HPLC on chiral phase by the method described in Example 4.The [(R,R)-Et-FerroTANE-Rh]BF₄ catalyst afforded the corresponding Rderivative in the same yield and enantiomeric purity.

ee: 87%

Example 5 Preparation of methyl (S)- and(R)-2-benzoylamino-3-diphenylaminopropionate

Analogously to Example 4, methyl 2-benzoylamino-3-diphenylaminoacrylatewas hydrogenated with various catalysts and solvents. In the case of thecatalysts which had not been prepared beforehand, the active catalystwas prepared in situ from the optically active phosphine ligand andequimolar amounts of [Rh(cod)Cl]₂ as the rhodium(l) salt. The resultsare compiled in Table 1 below.

TABLE 1 Rho- Pres- Conver- dium sure sion ee RCS Catalyst/ligand salt[bar] Solvent [%] [%] 1:100 [(R,R)-Et- no 20 Toluene 97 90FerroTANE-Rh]BF₄ [268220-96-8] 1:100 [(R,R)-Et- no 20 Methanol 95 RFerroTANE-Rh]BF₄ 87 [268220-96-8] 1:100 [(R,R)-Et- no 20 Dichloro- 97 85FerroTANE-Rh]BF₄ methane [268220-96-8] 1:100 [(S,S)-Et- no 20 Methanol94 S FerroTANE-Rh]BF₄ 86 [268220-96-8] 1:100 [(R,R)-Me- no 20 Toluene NCnd DUPHOS- Rh]CF₃SO₃ [136705-77-6] 1:100 [(R,R)-Me- no 20 Methanol 71 90DUPHOS- Rh]CF₃SO₃ [136705-77-6] 1:100 [(R,R)-Me- no 20 Dichloro- 65 86DUPHOS- methane Rh]CF₃SO₃ [136705-77-6] 1:100 (R)-(S)-JOSIPHOS yes 20Toluene 68 36 [155806-35-2] 1:100 (R)-(S)-JOSIPHOS yes 20 Methanol 91 31[155806-35-2] 1:100 (R)-(S)-JOSIPHOS yes 20 Dichloro- 82 11 methane1:100 L-BPPM-E yes 20 Toluene 21 68 [61478-28-2] 1:100 L-BPPM-E yes 20Methanol 80 35 [61478-28-2] 1:100 L-BPPM-E yes 20 Dichloro- 5 45[61478-28-2] methane 1:100 (S)-BINAPHANE yes 20 Toluene 37 6[544461-38-3] 1:100 (S)-BINAPHANE yes 20 Methanol 31 48 [544461-38-3]1:100 (S)-BINAPHANE yes 20 Dichloro- 19 46 [544461-38-3] methane 1:100(R)-(-)-tert-Ferro yes 20 Methanol 59 99 [155830-69-6] 1:100(R)-(-)-Cyclohexyl- yes 20 Methanol 11 99 Ferro [167416-28-6] 1:100(R,R)-BDPP yes 20 Methanol NC nd [96183-46-9] 1:100 (S,S)-CHIRAPHOS yes20 Methanol NC nd [64896-28-2] 1:100 (R,R)-DIOP yes 20 Methanol 5 95[32305-98-9] 1:100 (R)-PROPHOS yes 20 Methanol NC nd [67884-32-6] 1:100(S,S)-NORPHOS yes 20 Methanol NC nd [71042-55-2] 1:100 (R,R)-iPr-DUPHOSyes 20 Methanol 30 99 [136705-65-2] 1:100 [(R,R)-Et-BPE yes 20 Methanol62 99 [136705-62-9] 1:100 [(R,R)-Me-BPE- no 20 Methanol 55 96 Rh]CF₃SO₃[213343-69-2] 1:100 (R)-Me-BOPHOZ yes 20 Methanol NC nd [406680-93-1]1:100 MonoPhos yes 20 Methanol NC nd [157488-65-8] 1:100 MonoPhos yes 20Dichloro- NC nd [157488-65-8] methane 1:100 MonoPhos yes 20 Methanol NCnd [490023-37-5] 1:100 MonoPhos yes 20 Dichloro- NC nd [490023-37-5]methane 1:100 MonoPhos yes 20 Methanol NC nd [380230-02-4] 1:100MonoPhos yes 20 Dichloro NC nd [380230-02-4] methane RCS = Molar ratioof catalyst to substrate NC = No conversion nd = Not determined R or Sin the ″ee [%]″ column means the particular R or S enantiomer

Example 6

With exclusion of oxygen, an autoclave was charged with the amounts ofmethyl 2-benzoylamino-3-diphenylaminoacrylate and[(R,R)-Me-DUPHOS-Rh]CF₃SO₃ specified in Table 1. After purging withargon, the amount of oxygen-free methanol specified below was added. Theautoclave was sealed gas-tight and the solution was hydrogenated at 30bar of hydrogen pressure at RT for 20 h. The autoclave was decompressedand purged with nitrogen. The conversion of the hydrogenation wasdetermined by HPLC. The enantioselectivity was determined by HPLC onchiral phase by the method described in Example 4. The result is shownin Table 2.

Catalyst/ substrate Reactant Conversion ee ratio Catalyst [g] [%] [%]1:1000 [(R,R)-Me-DUPHOS- 26 25 87 Rh]CF₃SO₃

Example 7

With exclusion of oxygen, an autoclave was charged with the amounts ofmethyl 2-benzoylamino-3-diphenylaminoacrylate and[(S,S)-Et-FerroTANE-Rh]BF₄ specified in Table 2. After purging withargon, the amount of oxygen-free methanol specified below was added. Theautoclave was sealed gas-tight and the solution was hydrogenated at 30bar of hydrogen pressure at RT for 20 h. The autoclave was decompressedand purged with nitrogen. The solution was filtered, admixed with thesame amount of water at 40° C. and stirred at RT for 2 h. Thecrystallized product is filtered off with suction and dried to constantweight under reduced pressure at 45° C. The conversion of thehydrogenation was determined by HPLC. The enantioselectivity wasdetermined by HPLC on chiral phase by the method described in Example 4.The result is shown in Table 3.

TABLE 3 Con- Catalyst/sub- Reactant version ee Yield strate ratioCatalyst [g] [%] [%] [%] 1:1000 [(S,S)-Et-FerroTANE- 26 98 85 89 Rh]BF₄[268220-96-8] 1:2500 [(S,S)-Et-FerroTANE- 26 99 84 88 Rh]BF₄[268220-96-8] 1:5000 [(S,S)-Et-FerroTANE- 26 98 86 90 Rh]BF₄[268220-96-8] 1:10000 [(S,S)-Et-FerroTANE- 26 73 85 n.i. Rh]BF₄[268220-96-8] 1:5000 [(S,S)-Et-FerroTANE- 260 98 85 89 Rh]BF₄[268220-96-8]

Example 8

With exclusion of oxygen, an autoclave was charged with 1 g (2.68 mmol)of methyl 2-benzyloxycarbonylamino-3-diphenylaminoacrylate and 40 mg(0.042 mmol) of tris(triphenylphosphine)rhodium(l) chloride. Afterpurging with argon, 40 ml of oxygen-free methanol were added. Theautoclave was sealed gas-tight and the solution was hydrogenated at RTfor 20 h. The autoclave was decompressed and purged with nitrogen. Thesolvent was evaporated off under reduced pressure and the residue waspurified by means of a column filled with silica gel 60 (eluent: 1:1ethyl acetate/heptane). After the solvents had been evaporated off underreduced pressure, a white solid remained, which was utilized for theformulation of a method and as a system test for the determination ofthe enantiomeric purity by HPLC on chiral phase.

HPLC column: Chiralpak OD 4 × 250 Eluent: 50:2:1  hexane/EtOH/MeOH +0.1% diethylamine Temperature 30° C. Reactant retention time: 19.2minutes S-Isomer retention time: 14.6 minutes R-Isomer retention time:16.0 minutes Yield:  0.2 g (20% of theory) 1H NMR: 3.60 (s, 3H),3.95-4.15 (m, 2H), 4.35-4.45 (m, 1H), 4.92-5.05 (m, 2H), 6.90-7.00 (m,6H), 7.15-7.40 (m, 9H), 7.85-7.90 (d, 1H)

Example 9

Analogously to Example 5, methyl2-benzyloxycarbonylamino-3-diphenylaminoacrylate was hydrogenated withvarious catalysts and solvents. In the case of the catalysts which hadnot been prepared beforehand, the active catalyst was prepared in situfrom the optically active phosphine ligand and equimolar amounts of[Rh(cod)Cl]₂ as the rhodium(l) salt. The results are compiled in Table 4below.

TABLE 4 Rho- Pres- Conver- Catalyst/ dium sure sion ee RCS ligand salt[bar] Solvent [%] [%] 1:100 [(R,R)-Et- no 20 Toluene 15 43FerroTANE-Rh]BF₄ [268220-96-8] 1:100 [(R,R)-Et- no 20 Methanol 2 ndFerroTANE-Rh]BF₄ [268220-96-8] 1:100 [(R,R)-Et- no 20 Dichloro- 4 ndFerroTANE-Rh]BF₄ methane [268220-96-8] 1:100 [(R,R)-Me- no 20 Toluene 15nd DUPHOS- Rh]CF₃SO₃ [136705-77-6] 1:100 [(R,R)-Me- no 20 Methanol 25 61DUPHOS- Rh]CF₃SO₃ [136705-77-6] 1:100 [(R,R)-Me- no 20 Dichloro- 29 46DUPHOS- methane Rh]CF₃SO₃ [136705-77-6] 1:100 (R)-(S)-JOSIPHOS yes 20Toluene 13 nd [155806-35-2] 1:100 (R)-(S)-JOSIPHOS yes 20 Methanol 35 28[155806-35-2] 1:100 (R)-(S)-JOSIPHOS yes 20 Dichloro- 17 43[155806-35-2] methane 1:100 L-BPPM-E yes 20 Toluene 5 nd [61478-28-2]1:100 L-BPPM-E yes 20 Methanol 7 nd [61478-28-2] 1:100 L-BPPM-E yes 20Dichloro- 6 nd [61478-28-2] methane 1:100 (S)-BINAPHANE yes 20 Toluene<5 nd [544461-38-3] 1:100 (S)-BINAPHANE yes 20 Methanol <5 nd[544461-38-3] 1:100 (S)-BINAPHANE yes 20 Dichlor- <5 nd [544461-38-3]methane 1:100 [(R,R)-Me-BPE- no 20 Methanol 36 73 Rh]CF₃SO₃ 1:100(R)-(-)-tert-Ferro yes 20 Methanol 85 21 [155830-69-6] 1:100(R)-(S)-JOSIPHOS yes 20 Methanol 99 24 1:100 [(R,R)-Et- yes 20 Methanol52 60 FerroTANE-Rh]BF₄ 1:100 (R,R)-BDPP yes 20 Methanol NC nd[96183-46-9] 1:100 (S,S)-CHIRAPHOS yes 20 Methanol NC nd [64896-28-2]1:100 (R,R)-DIOP yes 20 Methanol NC nd [32305-98-9] 1:100 (R)-PROPHOSyes 20 Methanol NC nd [67884-32-6] 1:100 (S,S)-NORPHOS yes 20 MethanolNC nd [71042-55-2] 1:100 [(R,R)-Et-BPE- yes 20 Methanol 6 23 Rh]BF₄1:100 (R)-Me-BOPHOZ no 20 Methaol 25 16 (Eastman) RCS = Ratio ofcatalyst to substrate; NC = No conversion nd = Not determined; < = Lessthan

Example 10 Preparation of methyl(S)-2-(benzoyl-tert-butoxycarbonylamino)-3-diphenylam inopropionate

18.7 g of methyl(S)-2-(benzoyl-tert-butoxycarbonylamino)-3-diphenylaminopropionate,ee=85%, 20.6 of di-tert-butyl dicarbonate and 1.2 g ofN,N-dimethylaminopyridine were dissolved in 90 ml of acetonitrile andstirred at 40° C. for 3 hours. The acetonitrile was evaporated off underreduced pressure and the remaining residue was taken up in 300 ml ofdiisopropyl ether and hot-filtered. The product crystallized outovernight as a colorless solid.Yield: 23.7 g (88% of theory)1H NMR: 1.38 (s, 9H), 3.70 (s, 3H), 4.35-4.58 (m, 2H), 5.45-5.52 (m,1H), 6.93-7.05 (m, 6H), 7.13-7.18 (m, 2H), 7.22-7.30 (m, 4H), 7.32-7.30(m, 2H), 7.45-7.52 (m, 1 H)

Example 11 Preparation of methyl(S)-2-(tert-butoxycarbonylamino)-3-diphenylaminopropionate

1.3 g of methyl(S)-2-(benzoyl-tert-butoxycarbonylamino)-3-diphenylaminopropionate weredissolved in 13 ml of methanol and admixed with 2.74 ml of a 1M solutionof magnesium methoxide in methanol. The solution was stirred at RTovernight and concentrated under reduced pressure. The residue was takenup in ethyl acetate and washed with water. The ethyl acetate phase wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was crystallized from a little diisopropylether/heptane.Yield: 0.95 g (90% of theory)1H NMR: 1.38 (s, 9H), 3.55 (s, 3H), 4.10-4.25 (m, 2H), 4.50-4.62 (m,1H), 5.10-5.25 (m, 1H), 6.90-7.05 (m, 6H), 7.20-7.30 (m, 4H)

Example 12 Preparation of methyl (S)-2-amino-3-diphenylaminopropionatep-toluenesulfonate

18.5 g of methyl(S)-2-(tert-butoxycarbonylamino)-3-diphenylaminopropionate (ee=85%) weredissolved in 100 ml of dichloromethane and with and admixed with 50 mlof trifluoroacetic acid (TFA). The solution was heated under reflux for30 minutes and then concentrated to a volume of 100 ml under reducedpressure. The solution was washed with water and admixed with 9 g ofp-toluenesulfonic acid. 125 ml of n-butanol were added and the remainingdichloromethane was evaporated off. To crystallize the p-toluenesulfonicsalt, the solution was cooled to RT and stirred overnight. The solid wasfiltered off with suction and dried to constant weight under reducedpressure.Yield: 16.6 g (81% of theory, based on desired isomer)1H NMR: 2.38 (s, 3H), 3.30 (s, 3H), 4.10-4.35 (m, 3H), 5.45-5.52 (m,1H), 6.73-6.95 (m, 6H), 7.01-7.05 (m, 2H), 7.10-7.18 (m, 4H), 7.58-7.62(m, 2H), 8.30-8.55 (s, broad, 3H, NH)ee: 99%

Example 13 Preparation of methyl 2-benzoylamino-3-phenylaminoacrylate

10g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and11.1 g (118 mmol) of aniline were dissolved at 40° C. in 200 ml ofisopropanol. The solution was admixed with 3.6 ml (43.5 mmol) ofconcentrated hydrochloric acid within 5 minutes (min) and stirred for afurther 10 min. 200 ml of deionized water were added, the suspension wascooled to 10° C. and the crystallized product was filtered off.Yield: 11.5 g (92% of theory)1H NMR: 3.62 (s, 3H); 6.90-7.00 (m, 1H); 7.19 (d, 2H); 7.25-7.30 (m,2H); 7.48-7.61 (m, 3H); 7.93 (d, 1H); 8.02 (d, 2H); 8.90 (d, 1H); 9.15(s, 1H)

Example 14 Preparation of methyl2-benzoylamino-3-(4-fluorophenylamino)acrylate

10g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and11.4 ml (118 mmol) of 4-fluoroaniline were dissolved in 200 ml ofisopropanol at 40° C. The solution was admixed with 3.6 ml (43.5 mmol)of concentrated hydrochloric acid within 5 minutes (min) and stirred fora further 30 min. The suspension was cooled to 10° C. and thecrystallized product was filtered off.Yield: 12.4 g (94% of theory)1H NMR: 3.62 (s, 3H); 7.05-7.24 (m, 4H); 7.48-7.52 (m, 3H); 7.88 (d,1H); 8.00-8.04 (m, 2H); 8.90 (d, 1H); 9.15 (s, 1H)

Example 15 Preparation of methyl2-benzoylamino-3-(pyridin-2-ylamino)acrylate

10g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and11.3 g (118 mmol) of 2-aminopyridine were dissolved in 200 ml ofisopropanol at 40° C. The solution was admixed with 3.96 ml (48 mmol) ofconcentrated hydrochloric acid within 5 minutes (min) and stirred for afurther 30 min. The suspension was cooled to 10° C. and the crystallizedproduct was filtered off.Yield: 7.3 g (60% of theory)1H NMR: 3.62 (s, 3H); 6.92-6.97 (m, 1H); 7.02 (d, 1H); 7.45-7.70 (m,4H); 8.02 (d, 2H); 8.22-8.24 (m, 1H); 8.60 (d, 1H); 9.22 (s, 1 H); 9.45(d, 1 H)

Example 16 Preparation of methyl2-benzoylamino-3-(thiazol-2-ylamino)acrylate

10g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and11.3 g (118 mmol) of 2-aminothiazole were dissolved at 40° C. in 200 mlof isopropanol. The solution was admixed with 3.96 ml (48 mmol) ofconcentrated hydrochloric acid within 5 minutes (min) and stirred for afurther 60 min. 75 ml of deionized water were added, the suspension wascooled overnight and the crystallized product was filtered off.Yield: 8.6 g (70% of theory)1H NMR: 3.62 (s, 3H); 7.08 (d, 1H); 7.32 (d, 1H); 7.45-7.60 (m, 3H);8.02 (d, 2H); 8.22 (d, 1 H); 9.28 (s, 1 H); 10.45 (d, 1 H)

1. A compound of formula II:

where: R1 and R2 are the same or different and are each independently:—(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-, di- ortrisubstituted independently by R11, where R11 is: F, Cl, I or Br,—(C₁-C₄)-alkyl, —CN, —CF₃, —OR⁵ in which R⁵ is a hydrogen atom or—(C₁-C₄)-alkyl, —N(R⁵)—R⁶ in which R⁵ and R⁶ are each independently ahydrogen atom or —(C₁-C₄)-alkyl; —C(O)—R⁵ in which R⁵ is a hydrogen atomor —(C₁-C₄)-alkyl; or —S(O)_(x)—R⁵ in which x is the integer zero, 1 or2, and R⁵ is a hydrogen atom or —(C₁-C₄)-alkyl; or a 4- to 15-memberedHet ring where the Het ring is unsubstituted or mono-, di- ortrisubstituted independently by —(C₁-C₅)-alkyl, —(C₁-C₅)-alkoxy,halogen, nitro, amino, trifluoro-methyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl,cyano, hydroxycarbonyl, amino-carbonyl or —(C₁-C₄)-alkoxycarbonyl; R3is: —(C₆-C₁₄)-aryl in which aryl is unsubstituted or mono-, di- ortrisubstituted independently by —NO₂, —O—(C₁-C₄)-alkyl, F, Cl orbromine; —O—C(CH₃)₃; or —O—CH(R7)-aryl in which aryl is unsubstituted ormono-, di- or trisubstituted independently by —NO₂, —O—CH₃, F, Cl orbromine, in which R7 is a hydrogen atom or —(C₁-C₄)-alkyl; R4 is: ahydrogen atom; —(C₁-C₄)-alkyl; or —CH(R8)-aryl in which R8 is a hydrogenatom or —(C₁-C₄)-alkyl.
 2. A process for obtaining the compound of theformula II as claimed in claim 1, said process comprising the step of:reacting the compound of the formula VI:

in which R3 and R4 are each as defined in as follows: R3 is:—(C₆-C₁₄)-aryl in which aryl is unsubstituted or mono-, di- ortrisubstituted independently by —NO₂, —O—(C₁-C₄)-alkyl, F, Cl orbromine; —O—C(CH₃)₃; or —O—CH(R7)-aryl in which aryl is unsubstituted ormono-, di- or trisubstituted independently by —NO₂, —O—CH₃, F, Cl orbromine, in which R7 is a hydrogen atom or —(C₁-C₄)-alkyl; R4 is: ahydrogen atom; —(C₁-C₄)-alkyl; or —CH(R8)-aryl in which R8 is a hydrogenatom or —(C₁-C₄)-alkyl, with an amine of the formula V:R1—N(H)—R2  (V) in which R1 and R2 are each as defined as follows: R1and R2 are the same or different and are each independently:—(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-, di- ortrisubstituted independently by R11, where R11 is F, Cl, I or Br,—(C₁-C₄)-alkyl, —CN, —CF₃, —OR⁵ in which R⁵ is a hydrogen atom or—(C₁-C₄)-alkyl, —N(R⁵)—R⁶ in which R⁵ and R⁶ are each independently ahydrogen atom or —(C₁-C₄)-alkyl; —C(O)—R⁵ in which R⁵ is a hydrogen atomor —(C₁-C₄)-alkyl; or —S(O)_(x)—R⁵ in which x is the integer zero, 1 or2, and R⁵ is a hydrogen atom or —(C₁-C₄)-alkyl; or a 4- to 15-memberedHet ring where the Het ring is unsubstituted or mono-, di- ortrisubstituted independently by —(C₁-C₅)-alkyl, —(C₁-C₅)-alkoxy,halogen, nitro, amino, trifluoro-methyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl,cyano, hydroxycarbonyl, amino-carbonyl or —(C₁-C₄)-alkoxycarbonyl; togive the compound of the formula II.